Obstetrics & Gynecology:
Isolation of Herpes Simplex Virus From the Genital Tract During Symptomatic Recurrence on the Buttocks
Kerkering, Katrina MD2; Gardella, Carolyn MD, MPH4; Selke, Stacy MS, MA2; Krantz, Elizabeth MS2; Corey, Lawrence MD1,2,5; Wald, Anna MD, MPH1,2,3,5
From the Departments of 1Medicine, 2Laboratory Medicine, 3Epidemiology, and 4Obstetrics & Gynecology, University of Washington; and the 5Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Supported by NIH grant AI-3073/0.
Corresponding author: Carolyn Gardella, MD, MPH, University of Washington Department of Obstetrics & Gynecology, Box 356460, Seattle, WA 98195; e-mail: firstname.lastname@example.org.
Financial Disclosure Carolyn Gardella, MD, MPH is on the speakers’ bureau of GlaxoSmithKline but, to date, has received no financial compensation from GlaxoSmithKline. Lawrence Corey, MD directs the University of Washington Virology Laboratory which has acted as a reference laboratory for the diagnosis of HSV infections. The laboratory has received grant support from GlaxoSmithKline and Novartis, makers of antivirals for HSV. Dr Corey is a consultant to Antigenics regarding HSV candidate vaccines. Anna Wald, MD, MPH has received grant support from GlaxoSmithKline, Antigenics, Roche, Vical, and Ranbaxy. She is a consultant for and received honoraria from Novartis, Powdermed and Medigene.
OBJECTIVE: To estimate the frequency of isolation of herpes simplex virus (HSV) from the genital tract when recurrent herpes lesions were present on the buttocks.
METHODS: Data were extracted from a prospectively observed cohort attending a research clinic for genital herpes infections between 1975 and 2001. All patients with a documented herpes lesion on the buttocks, upper thigh or gluteal cleft (“buttock recurrence”) and concomitant viral cultures from genital sites including the perianal region were eligible.
RESULTS: We reviewed records of 237 subjects, 151 women and 86 men, with a total of 572 buttock recurrences. Of the 1,592 days with genital culture information during a buttock recurrence, participants had concurrent genital lesions on 311 (20%, 95% confidence interval [CI] 14–27%) of these days. Overall, HSV was isolated from the genital region on 12% (95% CI 8–17%) of days during a buttock recurrence. In the absence of genital lesions, HSV was isolated from the genital area on 7% (95% CI 4%–11%) of days during a buttock recurrence and, among women, from the vulvar or cervical sites on 1% of days.
CONCLUSION: Viral shedding of herpes simplex virus from the genital area is a relatively common occurrence during a buttock recurrence of genital herpes, even without concurrent genital lesions, reflecting perhaps reactivation from concomitant regions of the sacral neural ganglia. Patients with buttock herpes recurrences should be instructed about the risk of genital shedding during such recurrences.
LEVEL OF EVIDENCE: II-2
Herpes simplex virus (HSV) infections most commonly occur on the oral or genital mucosa. However, lesions also can occur at nonoral, nongenital sites.1 Among patients with primary genital herpes, 21% subsequently developed nongenital recurrences.2 Nongenital sites most often are the buttocks and legs, reflecting the distribution of the dorsal nerve root ganglia that innervate these areas.2 Thus, patients presenting with HSV lesions on the buttocks or thighs usually are advised that they have genital herpes because of the overlap between sacral nerve root innervation of the buttock and other regions of the genital tract. However, the risk of concomitant genital shedding of HSV-2 at the time of symptomatic reactivation at the buttocks has not been evaluated. Concomitant shedding would be medically important for prevention of sexual transmission of HSV to partners of men and women with recurrent buttock HSV and for management of women with buttock lesions at the time of labor.
To investigate whether isolation of HSV from genital sites is common during reactivation lesions on the buttocks we performed an analysis of the patients with buttock herpes who had samples obtained for HSV isolation during a buttock reactivation of HSV-2.
MATERIALS AND METHODS
The data for this study were extracted from a prospectively observed cohort of patients attending the University of Washington Virology Research Clinic between 1975 and 2001. The enrollment criteria and methods used for entering and observing such patients have been described previously.3 Briefly, the University of Washington Virology Research Clinic was established in 1975 as a referral research center for the study of genital herpes. Since inception it maintained a repository of clinical and laboratory data regarding patients participating in HSV-related studies. The data used for this study were derived from the database. The clinic uses standardized forms to collect clinical and demographic information at each visit. As such, data are consistent across study protocols. At the initial clinic visit, all herpetic lesions were described by anatomic site and lesion stage. In general, patients were then seen at 2–3 day intervals until lesions healed. Patients were requested to return at least every 2–3 months and at the time of recurrences. During patient follow-up, recurrences of lesions at all sites were documented.
Standardized information was collected on all clinic participants, including demographics, medical and sexual history, and human immunodeficiency virus (HIV) serostatus. Human immunodeficiency virus testing was offered to all participants, and subjects from high-risk groups were strongly encouraged to be tested for HIV. Participants had thorough genital examinations with independent samples collected for viral isolation from the cervix, vulva, urethra, and perianal area for women, and the penis, urethra and perianal area for men. Independent samples also were collected from lesions on the buttocks as well as any other lesions outside the genital area. Each sample was placed into an individual vial of culture media and plated separately for HSV isolation. Our standard approach to obtain samples for viral isolation from separate anatomic locations was to swab adjacent areas without overlapping. These procedures were approved by University of Washington institutional review board.
For this analysis, we selected participants who had at least one documented HSV recurrence on the buttocks during follow-up and had viral cultures obtained from genital sites at least once during the recurrence. Buttock lesions were defined as herpes lesions on the buttocks, upper thigh or gluteal cleft excluding the perianal region. Diagnosis of recurrent HSV on the buttocks was made on clinical grounds, regardless of whether a culture of the lesion was positive. Approximately 95% of recurrences were observed by study clinicians, whereas the other 5% were reported to the clinician by the patients. Dates of initiation and resolution of the recurrent lesion were noted by participants at home and documented in case report forms or documented by clinical examination. All lesions were considered to be part of the same recurrence if new lesions appeared before previous lesions healed.
Genital lesions were defined as herpes lesions on the vulva, perineal, or perianal area in women and penile or perianal area in men. Symptomatic genital HSV shedding was defined as at least one positive culture from one of the genital sites when genital lesions were noted, and subclinical genital shedding was defined as isolation of HSV from a genital site in the absence of genital lesions.
We excluded participants with newly acquired HSV-1 or HSV-2 because extragenital lesions are more common during primary genital herpes and are likely to be associated with a high frequency of isolation of HSV from the genital tract.2
Shedding rates were calculated on a per-day basis by dividing the number of days with a positive genital culture by the total number of days with genital culture obtained during a buttock recurrence. Confidence intervals for shedding or lesion rates were obtained using generalized estimating equations with binomial distribution and logit link to estimate the predicted probability of shedding (or lesions) and its associated variability. Intercept-only generalized estimating equation models4 were used for overall rates, and models with gender and HIV status main effects and interaction were used to calculate 95% confidence intervals specific to gender-HIV subgroups.
Viral isolation was performed as previously described, with typing of all isolates with monoclonal antibodies.5,6 This method was consistent throughout the study interval. The HSV-1 and HSV-2 serologic status was determined by HSV Western blot.7
The study population included 237 participants with buttock recurrences during which a sample for viral culture was obtained from the genitals on at least 1 day. One hundred fifty-one participants (64%) were women, and 86 participants (36%) were men; 93% were Caucasian (Table 1). Two of the 151 women were HIV seropositive, as were 29 of the 86 men. One hundred twenty-six participants (53%) were seropositive for HSV-2 only, 2 (1%) were seropositive for HSV-1 only, and 84 (35%) were seropositive for both HSV-1 and HSV-2. Twenty-five participants (11%) had unknown serology, because they participated in studies before the availability of serologic assays. These participants had clinical histories consistent with recurrent genital herpes.
The total number of buttock recurrences analyzed was 572 (368 in women and 204 in men), with a median of 1 recurrence per person (range 1–17). Among a subset of 484 recurrences with known durations, the median duration of a buttock recurrence among women was 9 days (range 1–89 days) and among men was 10 days (range 1–38 days). The median duration of buttocks recurrence was 9 days both in persons with and without HIV infection. During the median 9 days of buttocks recurrence, genital samples were collected on 1 day for 60% of recurrences, on 2–3 days for 12% of recurrences, on 4–5 days for 11% of recurrences, on 6–9 days for 11% of recurrences, and on more than 9 days for 6% of recurrences. In 9% of buttocks recurrences, a viral culture was obtained from the genital area throughout the duration of the recurrence. Of the remaining recurrences, viral cultures were collected from the genital area on a median of 14.3% (range 1.7–94.4%) of days of the buttocks recurrences.
Herpes simplex virus was detected in the genital tract during a buttocks recurrence in 69 of 237 (29%) persons. Among 178 people with one to seven genital cultures obtained during a buttocks recurrence, 39 (22%) had at least one positive genital culture. Among the remaining 59 people with seven to 75 genital cultures collected during an episode of buttocks lesions, 30 (51%) had at least one positive genital culture. Of the total 572 episodes of HSV recurrence on the buttocks, 89 (16%) had at least 1 day with HSV detected in the genital sites. For the majority of these buttock recurrences with genital shedding, HSV-2 was detected (79%). The remaining recurrences with genital shedding were either HSV-1 (2%) or unknown type (19%) (Fig. 1).
Viral cultures from a genital site were obtained on a total of 1592 days during buttock recurrences. HSV was isolated from the genitals on 12% (95% confidence interval [CI] 8–17%) of days on which samples for culture were collected, and genital lesions were noted on 20% (95% CI 14–27%) of all days. The genital shedding rate did not vary significantly by the sampling frequency (data not shown).
In the absence of genital lesions, HSV was isolated from genital samples collected on 86 of 1,281 days (7% [95% CI 4–11%], Table 2). Among HIV seronegative participants, subclinical genital shedding rate during a buttock recurrence was 7% (95% CI 3–14%) for women and 5% (95% CI 3–8%) for men. For HIV seropositive men, subclinical shedding occurred on 16 of 165 days (10%, 95% CI 3–31%) during a buttock recurrence.
We further described subclinical genital shedding of HSV during a buttock recurrence by examining viral isolation rates from specific genital sites. We restricted these data to days with culture results for the vulva, cervix, and perianal area for women and days with culture results for the penile and perianal area for men, and used days without genital lesions only. Among HIV seronegative women, observed rates of subclinical shedding were greatest from the perianal area, with HSV detected from this site alone on 40 (8%) of 524 days. Subclinical shedding from the vulva or cervix was less common; HSV was detected from the vulva or cervix sites on 1% of days. Similarly, in HIV seronegative men, subclinical shedding from the perianal area was more common than subclinical shedding from the penile area; on 13 of 329 (4%) days, HSV was detected from the perianal area only compared with 0.3% of days from the penile area only. Herpes simplex virus seropositive men showed a similar pattern, with HSV detected in the perianal area alone on 9% days compared with 0.6% of days for penile area alone.
Our data indicate that concomitant genital shedding frequently accompanies HSV-2 reactivation in the buttock area. This concomitant reactivation was seen in both HIV-negative and HIV-positive persons and was similar for men (14% of days with genital culture) and women (10% of days). Thus, patients should avoid sexual contact involving the genital area during nongenital site recurrences to prevent transmission of infection. Of interest, among women with buttock reactivation, perianal shedding of HSV-2 was the predominant anatomic site of concomitant reactivation of HSV-2. The distribution of the sacral nerve makes concomitant perianal shedding during an HSV recurrence on the buttocks biologically plausible. Whether perianal shedding is more or less efficient than vulvar shedding for sexual transmission of HSV-2 is unknown.
Neonatal herpes most commonly is caused by neonatal exposure to HSV in genital secretions during vaginal delivery, and isolation of HSV from genital secretions at the time of delivery is the major risk factor for neonatal HSV acquisition.8 Women with genital shedding of HSV at delivery have a 300-fold higher risk of transmitting the virus to their infants than women without genital shedding, and 5% of women who have HSV isolated from the vulva or cervix at the time of delivery infect their infants.8 Although clinical examination is relatively inaccurate to identify HSV in the genital tract at the time of labor,9 the American College of Obstetrics and Gynecology recommends Cesarean delivery to prevent neonatal herpes when genital lesions are present at the time of labor.10 Our study highlights the importance of a careful vulvovaginal examination for women presenting in labor with buttocks lesions because genital lesions that would suggest the need for cesarean delivery may be present 20% of the time.
The American College of Obstetrics and Gynecology does not recommend cesarean delivery for women with isolated herpes lesions of the buttocks or thigh at the time of labor, citing a possible 2% risk of neonatal exposure to HSV in genital secretions in this situation.10 Wittek et al11 reported subclinical shedding of HSV from the cervix in one of 47 (2.1%) pregnant women with nongenital lesions, a rate similar to seven of 299 (2.3%) pregnant women with a history of genital herpes and asymptomatic HSV shedding from the genitals. Harger et al12 reported subclinical cervical shedding in none of 60 pregnant women with nongenital lesions and 27 of 1,460 (1.9%) pregnant women with a history of genital herpes but without genital lesions at delivery. Thus, the American College of Obstetricians and Gynecologists found it justifiably safe to allow women with buttocks lesions to proceed with vaginal delivery.
Our findings concur with the low rate of HSV isolation from the cervix during a buttock recurrence. However, the rate of HSV isolation from the perineal region in women with buttock recurrence is relatively high and arguably may expose the neonate to HSV during vaginal delivery. Previous natural history studies of the risk of neonatal HSV included genital specimens collected from the cervix and vulva with the perianal region included as part of the vulvar sample.8,13 Thus, the implications of HSV isolation from the perianal region alone for neonatal HSV have not been determined and future studies to determine the risk of neonatal exposure and transmission in this situation are warranted.
There are several study limitations that merit discussion. We likely have underestimated the rate of shedding of HSV from the genital tract during recurrences on the buttocks because our detection method was limited to viral culture rather than polymerase chain reaction, a test up to four times more sensitive than viral culture.14 Further, in many cases genital samples were not collected daily during a buttocks recurrence, and it is likely that with increased frequency of observation greater numbers of people would have contributed at least one genital sample with HSV detected. However, increased sampling frequency would be unlikely to affect our reported genital shedding rates per days of observation. Analysis of proportion of days with a positive genital culture result by the proportion of days during a buttocks HSV recurrence that genital cultures were obtained revealed no systematic relationship suggesting that our estimated day-level shedding rates were not biased by the sampling frequency. Reliance on self-report of lesion recurrence is a potential study limitation; however, previous studies of this population found the data to be quite accurate as compared with recurrences verified by clinicians.15–18
Comparison of our data with previous reports of HSV isolation from the genital tract among pregnant women with recurrent lesions on the buttock must be done with care to note whether the data are presented at the person-level or as the percentage of days. Our study included many participants who contributed multiple observations, and at least 1 day of shedding was more likely to be observed in those who obtained more samples. This suggests that intermittent genital shedding occurs in many, if not most, persons who have buttocks recurrences. Further, the definitions of genital and nongenital recurrence vary among previous reports. Reports by Harger et al11 and Wittek et al12 specifically examine isolation of HSV from the cervix only during recurrent nongenital lesions. Witteck defines nongenital lesions as those on the buttocks, thigh, back or perianal region. Harger defined nongenital lesions as those on the buttocks, back or proximal thighs. Our definition included the buttocks, upper thigh and gluteal cleft, excluding the perianal region in women and the penile and perianal regions for men. We chose to include the perianal region as part of the genitals because of the close proximity and frequent contact with the perianal area during genital intercourse. Herpes simplex virus isolation from the perianal site is a risk factor for sexual transmission of HSV, especially among men who have sex with men.19
In summary, men and women with recurrent herpes lesions in the distribution of the dorsal nerve root should be advised that they are at risk for concomitant HSV isolation from genital secretions. Safer sex practices should include avoidance of contact with the genital and perianal region during recurrences on the buttocks, and clinicians who care for pregnant women in labor should be aware of the risk of genital tract HSV associated with recurrent lesions on the buttocks.
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